Evaluation of the Adverse Effects of Bosentan in Combination with Clarithromycin

The elimination of bosentan (BOSE) is involved in several metabolic enzymes and transporters, including CYP3A4 and OATP1B1/3. Clarithromycin (CAM) has the potential to inhibit these activities, leading to an approximately threefold increase in BOSE exposure when combined. Hepatic impairment, a common adverse effect of BOSE, is reportedly induced in a dose-dependent manner. This study comprehensively evaluated the adverse events of BOSE in combination with CAM. A total of 12 patients who received BOSE and CAM for more than 7 days at Oita University Hospital between June 2005 and December 2022 were included. The adverse events documented in the BOSE clinical trial were not observed within the 2-week period following the initiation of combination therapy. None of the patients exhibited an increase exceeding threefold the institutional reference threshold, which serves as the standard for BOSE suspension or discontinuation. No patient experienced a rise in liver function parameters necessitating the suspension or discontinuation of BOSE within 180 days of initiating the combination therapy. The findings suggest that concurrent use of BOSE and CAM does not increase the incidence of adverse events, including liver impairment. However, given that the daily dose in this study was approximately half the usual dose, caution is necessary when administering BOSE at the usual maintenance dose.